Okamoto model for necrosis and its expansions, CD38-cyclic ADP-ribose signal system for intracellular Ca<sup>2+</sup> mobilization and Reg (<b><i>Re</i></b><i>generating</i> <b><i>g</i></b><i>ene</i> protein)-Reg receptor system for cell regeneration
Hiroshi Okamoto, Shin Takasawa
Abstract
In pancreatic islet cell culture models and animal models, we studied the molecular mechanisms involved in the development of insulin-dependent diabetes. The diabetogenic agents, alloxan and streptozotocin, caused DNA strand breaks, which in turn activated poly(ADP-ribose) polymerase/synthetase (PARP) to deplete NAD+, thereby inhibiting islet β-cell functions such as proinsulin synthesis and ultimately leading to β-cell necrosis. Radical scavengers protected against the formation of DNA strand breaks and inhibition of proinsulin synthesis. Inhibitors of PARP prevented the NAD+ depletion, inhibition of proinsulin synthesis and β-cell death. These findings led to the proposed unifying concept for β-cell damage and its prevention (the Okamoto model). The model met one proof with PARP knockout animals and was further extended by the discovery of cyclic ADP-ribose as the second messenger for Ca2+ mobilization in glucose-induced insulin secretion and by the identification of Reg (Regenerating gene) for β-cell regeneration. Physiological and pathological events found in pancreatic β-cells have been observed in other cells and tissues.